Fluconazole 50mg Capsules
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Fluconazole 50mg Capsules
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each capsule contains 50mg fluconazole.
For excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Capsules, hard.
Fluconazole 50mg Capsules are green-white capsules.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Therapy may be started before the results of the cultures and other laboratory studies are known; however, once results become available, anti-infective therapy should be adjusted accordingly.
Fluconazole is indicated for the treatment of the following conditions:
1. Genital candidiasis. Vaginal candidiasis, acute or recurrent. Candidal balanitis. The treatment of partners who present with symptomatic genital candidiasis should be considered.
2. Mucosal candidiasis. These include oropharyngeal, oesophageal, non-invasive bronchopulmonary infections, candiduria, mucocutaneous and chronic oral atrophic candidiasis (denture sore mouth). Normal hosts and patients with compromised immune function may be treated.
3. Tinea pedis, tinea corporis, tinea cruris, tinea versicolor and dermal Candida infections. Fluconazole is not indicated for nail infections.
4. Systemic candidiasis including candidaemia, disseminated candidiasis and other forms of invasive candidal infection. These include infections of the peritoneum, endocardium and pulmonary and urinary tracts. Candidal infections in patients with malignancy, in intensive care units or those receiving cytotoxic or immunosuppressive therapy may be treated.
5. Cryptococcosis, including cryptococcal meningitis and infections of other sites (e.g. pulmonary, cutaneous). Normal hosts, and patients with AIDS, organ transplants or other causes of immunosuppression may be treated. Fluconazole can be used as maintenance therapy to prevent relapse of cryptococcal disease in patients with AIDS.
6. For the prevention of fungal infections in immunocompromised patients considered at risk as a consequence of neutropenia following cytotoxic chemotherapy or radiotherapy, including bone marrow transplant patients.
4.2 Posology and method of administration
Fluconazole may be administered either orally or by intravenous infusion at a rate of approximately 5-10ml/min, the route being dependent on the clinical state of the patient. On transferring from the intravenous route to the oral route or vice versa, there is no need to change the daily dose.
The daily dose of fluconazole should be based on the nature and severity of the fungal infection. Most cases of vaginal candidiasis respond to single dose therapy. Therapy for those types of infections requiring multiple dose treatment should be continued until clinical parameters or laboratory tests indicate that active fungal infection has subsided. An inadequate period of treatment may lead to the recurrence of active infection. Patients with AIDS and cryptococcal meningitis usually require maintenance therapy to prevent relapse.
Adults
1. Candidal vaginitis or balanitis - 150mg single oral dose.
2. Mucosal candidiasis - the usual dose is 50mg once daily for 7 - 14 days. Treatment should not normally exceed 14 days except in severely immunocompromised patients.
- Atrophic oral candidiasis associated with dentures - the usual dose is 50mg once daily for 14 days administered concurrently with local antiseptic measures to the denture.
- For other candidal infections of mucosa (except genital candidiasis see above), e.g. oesophagitis, non-invasive bronchopulmonary infections, candiduria, mucocutaneous candidiasis etc., the usual effective dose is 50mg daily, given for 14 - 30 days.
- In unusually difficult cases of mucosal candidal infections the dose may be increased to 100mg daily.
3. For tinea pedis, corporis, cruris, versicolor and dermal Candidal infections the recommended dosage is 50 mg once daily. Duration of treatment is normally 2 to 4 weeks but tinea pedis may require treatment for up to 6 weeks. Duration of treatment should not exceed 6 weeks.
4. For candidaemia, disseminated candidiasis and other invasive candidal infections the usual dose is 400mg on the first day followed by 200mg daily. Depending on the clinical response the dose may be increased to 400mg daily. Duration of treatment is based upon the clinical response.
5a. For cryptococcal meningitis and cryptococcal infections at other sites, the usual dose is 400mg on the first day followed by 200 - 400mg once daily. Duration of treatment for cryptococcal infections will depend on the clinical and mycological response, but is usually at least 6 - 8 weeks for cryptococcal meningitis.
5b. For the prevention of relapse of cryptococcal meningitis in patients with AIDS, after the patient receives a full course of primary therapy, fluconazole may be administered indefinitely at a daily dose of 100 - 200mg.
6. For the prevention of fungal infections in immunocompromised patients considered at risk as a consequence of neutropenia following cytotoxic chemotherapy or radiotherapy, the dose should be 50 to 400mg once daily, based on the patient’s risk for developing fungal infection. For patients at high risk of systemic infection e.g. patients who are anticipated to have profound or prolonged neutropenia such as during bone marrow transplantation, the recommended dose is 400mg once daily. Fluconazole administration should start several days before the anticipated onset of neutropenia, and continue for 7 days after the neutrophil count rises above 1000 cells per mm3.
Children
As with similar infections in adults, the duration of treatment is based on the clinical and mycological response. Fluconazole is administered as a single daily dose each day.
Children over four weeks of age The recommended dose of fluconazole for mucosal candidiasis is 3mg/kg daily. A loading dose of 6mg/kg may be used on the first day to achieve steady state levels more rapidly.
For the treatment of systemic candidiasis and cryptococcal infection, the recommended dosage is 6 - 12mg/kg daily, depending on the severity of the disease.
For the prevention of fungal infections in immunocompromised patients considered at risk as a consequence of neutropenia following cytotoxic chemotherapy or radiotherapy, the dose should be 3 - 12mg/kg daily, depending on the extent and duration of the induced neutropenia (see adult dosing).
A maximum dosage of 400mg daily should not be exceeded in children.
Despite extensive data supporting the use of fluconazole in children there are limited data available on the use of fluconazole for genital candidiasis in children below 16 years. Use at present is not recommended unless antifungal treatment is imperative and no suitable alternative agent exists.
Children below 4 weeks of age Neonates excrete fluconazole slowly. In the first two weeks of life the same mg/kg dosing as in older children should be used but administered every 72 hours. During weeks 2 - 4 of life the same dose should be given every 48 hours.
A maximum dosage of 12 mg/kg every 72 hours should not be exceeded in children below two weeks of life. For children between 2 - 4 weeks of life 12 mg/kg every 48 hours should not be exceeded.
For children with impaired renal function the daily dose should be reduced in accordance with the guidelines given for adults.
To facilitate accurate measurement of doses less than 10 mg, fluconazole should only be administered to children in hospital using preparations available as oral suspension or intravenous infusion, depending on the clinical condition of the child.
Elderly
The normal dose should be used if there is no evidence of renal impairment. In patients with renal impairment (creatinine clearance less than 50ml/min) the dosage schedule should be adjusted as described below.
Use in renal impairment
Fluconazole is excreted predominantly in the urine as unchanged drug. No adjustments in single dose therapy are required. In patients with impaired renal function who will receive multiple doses of fluconazole, the normal recommended dose (according to indication) should be given on day 1, followed by a daily dose based on the following table:
|
Creatinine clearance (ml/min) |
Percent of recommended dose |
|
> 50 |
100% |
|
11 -50 |
50% |
|
Patients receiving regular dialysis |
One dose after every dialysis session |
4.3 Contraindications
Fluconazole should not be used in patients with any known hypersensitivity to fluconazole or to related azole compounds or to any other ingredient within the formulation (see section 6.1.).
Co-administration with terfenadine or cisapride is contraindicated in patients receiving fluconazole at multiple doses of 400 mg per day or hugher based upon results of a multiple dose interaction study. Co-administration of other drugs known to prolong the QT interval and which are metabolized via the enzyme CYP3A4 such as cisapride, astemizole, primozide and quinidine are contraindicated in patients receiving fluconazole (see section 4.4 Special Warnings and Special Precautions for Use and 4.5 ‘Interaction with other medicinal products and other forms of interaction’.
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose - galactose malabsorption should not take this medicine.
4.4 Special warnings and precautions for use
In some patients, especially those with serious underlying diseases such as AIDS and cancer, abnormalities in haematological, hepatic, renal and other biochemical function test results have been observed during treatment with fluconazole but the clinical significance and relationship to treatment is uncertain.
Fluconazole should be administered with caution in patients with liver dysfunction (see also 4.2).
Very rarely, patients who died with severe underlying disease and who had received multiple doses of fluconazole had post-mortem findings which included hepatic necrosis. These patients were receiving multiple concomitant medications, some known to be potentially hepatotoxic, and/or had underlying diseases which could have caused the hepatic necrosis.
In cases of hepatotoxicity, no obvious relationship to total daily dose of fluconazole, duration of therapy, sex or age of the patient has been observed; the abnormalities have usually been reversible on discontinuation of fluconazole therapy.
Since a causal relationship with fluconazole cannot be excluded, patients who develop abnormal liver function tests during fluconazole therapy should be monitored for the development of more serious hepatic damage. Fluconazole should be discontinued if clinical signs or symptoms consistent with liver disease develop during treatment with fluconazole.
Patients have rarely developed exfoliative cutaneous reactions, such as Stevens-Johnson Syndrome and toxic epidermal necrolysis, during treatment with fluconazole. AIDS patients are more prone to the development of more severe cutaneous reactions to many drugs.
If a rash develops in a patient treated for a superficial fungal infection which may be attributed to fluconazole, further therapy with this agent should be discontinued. If patients with invasive / systemic fungal infections develop rashes, they should be monitored closely and fluconazole discontinued if bullous lesions or erythema multiforme develop.
The coadministration of fluconazole at doses lower than 400 mg per day with terfenadine should be carefully monitored (see section 4.3 Contraindications and 4.5 Interaction with Other Medicaments and Other Forms of Interaction).
In rare cases, as with other azoles, anaphylaxis has been reported.
Some azoles including fluconazole, have been associated with prolongation of the QT interval on the electrocardiogram. During post-marketing surveillance, there have been very rare cases of QT prolongation and torsade de pointes in patients taking fluconazole. These reports included seriously ill patients with multiple confounding risk factors, such as structural heart disease, electrolyte abnormalities and concomitant medications that may have been contributory.
Fluconazole should be administered with caution to patients with these potentially proarryhthmic conditions.
Fluconazole should be administered with caution to patients with renal dysfunction (see also 4.2).
Fluconazole is a potent CYP2C9 inhibitor and moderate CYP3A4 inhibitor. Fluconazole treated patients who are concomitantly treated with drugs with a narrow therapeutic window metabolised through CYP2C9 and CYP3A4, should be monitored (see section 4.5 Interaction with Other Medicaments and Other Forms of Interaction).
Flucoanzole 50mg Capsules contain lactose and should not be given to patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption.
4.5 Interaction with other medicinal products and other forms of interaction
The following drug interactions relate to the use of multiple-dose fluconazole, and the relevance to single-dose fluconazole has not yet been established:
Concomitant use of the following other medicinal products is contraindicated:
Cisapride
There have been reports of cardiac events including Torsades de Pointes in patients to whom fluconazole and cisapride were co-administered. In most of these cases, the patients appear to have been predisposed to arrhythmias or had serious underlying illnesses, and the relationship of the reported events to a possible fluconazole-cisapride drug interaction is unclear. A controlled study found that concomitant fluconazole 200 mg once daily and cisapride 20 mg four times a day yielded significant increase in cisapride plasma levels and prolongation of QT interval. Because of the potential seriousness of such an interaction, co-administration of cisapride is contraindicated in patients receiving fluconazole. (see section 4.3 Contraindications.)
Terfenadine
Because of the occurrence of serious dysrhythmias secondary to prolongation of the QTc interval in patients receiving other azole antifungals in conjunction with terfenadine, interaction studies have been performed. One study at a daily dose of 200mg of fluconazole failed to demonstrate a prolonged QTc interval. Another study at a 400mg and 800mg daily dose of fluconazole demonstrated that fluconazole taken in multiple doses of 400mg per day or greater did significantly increase plasma levels of terfenadine when taken concomitantly. There have been spontaneously reported cases of palpitations, tachycardia, dizziness, and chest pain in patients taking concomitant fluconazole and terfenadine where the relationship of the reported adverse events to drug therapy or underlying medical conditions was unclear. The combined use of fluconazole at doses of 400 mg or greater with terfenadine is contraindicated (see section 4.3 Contraindications). The coadministration of fluconazole at doses lower than 400 mg per day with terfenadine should be carefully monitored.
Astemizole
Concomitant administration of fluconazole with astemizole may decrease the clearance of astemizole. Resulting increased plasma concentrations of astemizole can lead to QT prolongation and rare occurrences of torsade de pointes. Coadministration of fluconazole and astemizole is contraindicated.
Pimozide
Although not studied in vitro or in vivo, concomitant administration of fluconazole with pimozide may result in inhibition of pimozide metabolism. Increased pimozide plasma concentrations can lead to QT prolongation and rare occurrences of torsade de pointes. Coadministration of fluconazole and pimozide is contraindicated.
Concomitant use of the following other medicinal products cannot be recommended:
Erythromycin
Concomitant use of fluconazole and erythromycin has the potential to increase the risk of cardiotoxicity (prolonged QT interval, Torsade de Pointes) and consequently sudden heart death. The combination should be avoided.
Concomitant use of the following other medicinal products lead to precautions and dose adjustments:
The effect of other medicinal products on fluconazole
Hydrochlorothiazide
In a pharmacokinetic interaction study, co-administration of multiple-dose hydrochlorothiazide to healthy volunteers receiving fluconazole increased plasma concentrations of fluconazole by 40%. An effect of this magnitude should not necessitate a change in the fluconazole dose regimen in subjects receiving concomitant diuretics, although the prescriber should bear it in mind.
Rifampicin
Concomitant administration of fluconazole and rifampicin resulted in a 25% decrease in the AUC and 20% shorted half-life of fluconazole. In patients receiving concomitant rifampicin, an increase in the fluconazole dose should be considered.
The effect of fluconazole on other medicinal products
Alfentanil
A study observed a reduction in clearance and distribution volume as well as prolongation of T1/2 of Alfentanil following concomitant treatment with fluconazole. A possible mechanism of action is fluconazole’s inhibition of CYP3A4. Dosage adjustment of Alfentanil may be necessary.
Amitriptyline, nortriptyline
Fluconazole increases the effect of amitriptyline and nortriptyline. 5-nortriptyline and/or S-amitriptyline may be measured at initiation of the combination therapy and after one week. Dosage of amitriptyline/nortriptyline should be adjusted, if necessary.
Amphotericin B
Concurrent administration of fluconazole and amphotericin B in infected normal and immunosuppressed mice showed the following results: a small additive antifungal effect in systemic infection with C. albicans, no interaction in intracranial infection with Cryptococcus neoformans, and antagonism of the two drugs in systemic infection with A. fumigates. The clinical significance of results obtained in these studies is unknown.
Anticoagulants
In an interaction study, fluconazole increased the prothrombin time (12%) after warfarin administration in healthy males. In postmarketing experience, as with other azole antifungals, bleeding events (bruising, epistaxis, gastrointestinal bleeding, hematuria and melaena) have been reported in association with increases in prothrombin time in patients receiving fluconazole concurrently with warfarin. Prothrombin time in patients receiving coumarin-type anticoagulants should be carefully monitored. Dose adjustment of warfarin may be necessary.
Azithromycin
An open-label, randomized, three-way crossover study in 18 healthy subjects assessed the effect of a single 1200 mg oral dose of azithromycin on the pharmacokinetics of a single 800 mg oral dose of fluconazole as well as the effects of fluconazole on the pharmacokinetics of azithromycin. There was no significant pharmacokinetic interaction between fluconazole and azithromycin.
Benzodiazepines (Short Acting)
Following oral administration of midazolam, fluconazole resulted in substantial increases in midazolam concentrations and psychomotor effects. This effect on midazolam appears to be more pronounced following oral administration of fluconazole than with fluconazole administered intravenously. If concomitant benzodiazepine therapy is necessary in patients being treated with fluconazole, consideration should be given to decreasing the benzodiazepine dosage and the patients should be appropriately monitored.
Fluconazole increases the AUC of triazolam (single dose) by approximately 50%, Cmax with 20 -32% and increases ti/2 by 25 - 50% due to the inhibition of metabolism of triazolam. Dosage adjustments of triazolam may be necessary.
Carbamazepine
Fluconazole inhibits the metabolism of carbamazepine and an increase in serum Carbamazepine of 30% has been observed. There is a risk of developing carbamazepine toxicity. Dosage adjustment of carbamazepine may be necessary depending on concentration measurements/effect.
Calcium Channel Blockers
Certain dihydropyridine calcium channel antagonists (nifedipine, isradipine, amlodipine and felodipine) are metabolised by CYP3A4. Fluconazole has the potential to increase the systemic exposure of the calcium channel antagonists. Frequent monitoring for adverse events is recommended.
Celecoxib
During concomitant treatment with fluconazole (200 mg daily) and celecoxib (200 mg) the celecoxib Cmax and AUC increased by 68% and 134% respectively. Half of the celecoxib dose may be necessary when combined with fluconazole.
Ciclosporin
Fluconazole significantly increases the concentration and AUC of ciclosporin. This combination may be used by reducing the dosage of ciclosporin depending on ciclosporin concentration. A kinetic study in renal transplant patients found fluconazole 200mg daily to slowly increase ciclosporin concentrations. However, in another multiple dose study with 100mg daily, fluconazole did not affect ciclosporin levels in patients with bone marrow transplants. Ciclosporin plasma concentration monitoring in patients receiving fluconazole is recommended.
Cyclophosphamide
Combination therapy with cyclophosphamide and fluconazole results in an increase in serum bilirubin and serum creatinine. The combination may be used while taking increased consideration to he risk of increased serum bilirubin and serum creatinine.
Fentanyl
One fatal case of possible fentanyl fluconazole interaction was reported. The author judged that the patient died from fentanyl intoxication. Furthermore, in a randomized crossover study with twelve healthy volunteers it was shown that fluconazole delayed the elimination of fentanyl significantly. Elevated fentanyl concentration may lead to respiratory depression.
Halofantrine
Fluconazole can increase halofantrine plasma concentration due to an inhibitory effect on CYP3A4.
HMG-CoA reductase inhibitors
The risk of myopathy and rhabdomyolysis increases when fluconazole is coadministered with HNMG-CoA reductase inhibitors metabolised through CYP3A4, such as atorvastatin and simvastatin, or through CYP2C9, such as fluvastatin. If concomitant therapy is necessary, the patient should be observed for symptoms of myopathy and rhabdomyolysis and creatinine kinase should be monitored. HMG-CoA reductase inhibitors should be discontinued if a marked increase in creatinine kinase is observed or myopathy/rhabdomyolysis is diagnosed or suspected.
Losartan
Fluconazole inhibits the metabolism of losartan to its active metabolite (E-31 74) which is responsible for most of the angiotensin II-receptor antagonism wich occurs during treatment with losartan. Patients should have their blood pressure monitored continuously.
Methadone
Fluconazole may enhance the serum concentration of methadone. Dosage adjustment of methadone may be necessary.
Non-steroidal anti-inflammatory drugs
The Cmax and AUC of flurbiprofen was increased by 23% and 81% respectively, when coadministered with fluconazole compared to administration of flurbiprofen alone. Similarly the Cmax and AUC of the pharmacologically active isomer [S-(+)-ibuprofen] was increased by 15% and 82% respectively, when fluconazole was coadministered with racemic ibuprofen (400 mg) compared to administration of racemic ibuprofen alone.
Although not specifically studied, fluconazole has the potential to increase the systemic exposure of other NSAIDs that are metabolized by CYP2C9 (e.g. naproxen, lornoxicam, meloxicam, diclofenac). Frequent monitoring for adverse events and toxicity related to NSAIDs is recommended. Adjustment of dosage of NSAIDs may be needed.
Oral contraceptives
Two pharmacokinetic studies with combined oral contraceptives have been performed using multiple doses of fluconazole. There were no relevant effects on either hormone level in the 50mg fluconazole study, while at 200mg daily the AUCs of ethinyloestradiol and levonorgestrel were increased 40% and 24% respectively. Thus multiple dose use of fluconazole at these levels is unlikely to have an effect on the efficacy of the combined oral contraceptive.
Phenytoin
Fluconazole inhibits the hepatic metabolism of phenytoin. With coadministration, serum phenytoin concentration levels should be monitored in order to avoid phenytoin toxicity. Concomitant administration of fluconazole and phenytoin may increase levels of phenytoin to a clinically significant degree. If it is necessary to administer both drugs concomitantly, phenytoin levels should be monitored and the phenytoin dose adjusted to maintain therapeutic levels.
Prednisone
There was a case report that a liver-transplanted patient treated with prednisone developed acute adrenal cortex insufficiency when a three month therapy with fluconazole was discontinued. The discontinuation of fluconazole presumably caused an enhanced CYP3A4 activity which led to increased metabolism of prednisone. Patients on long-term treatment with fluconazole and prednisone should be carefully monitored for adrenal cortex insufficiency when fluconazole is discontinued.
Rifabutin
There have been reports that an interaction exists when fluconazole is administered with rifabutin, leading to increased serum levels of rifabutin (increase in AUC up to 80%). There have been reports of uveitis in patients to whom fluconazole and rifabutin were co-administered. Patients receiving the two concomitantly should be carefully monitored.
Saquinavir
Fluconazole increases the AUC of saquinavir with approximately 50%, Cmax with approximately 55% and decreases clearance of saquinavir with approximately 50% due to inhibition of saquinavir’s hepatic metabolism by CYP3A4 and inhibition of P-glycoprotein. Dosage adjustment of saquinavir may be necessary.
Sirolimus
Fluconazole increases plasma concentrations of sirolimus presumably by inhibiting the metabolism of sirolimus via CYP3A4 and P-glycoprotein. This combination may be used with a dosage adjustment of sirolimus depending on the effect/concentration measurements.
Sulphonylureas
Fluconazole has been shown to prolong the serum half-life of concomitantly administered oral sulphonylureas (chlorpropamide, glibenclamide, glipizide and tolbutamide) in healthy volunteers. Fluconazole and oral sulphonylureas maybe co-administered to diabetic patients, but the possibility of a hypoglycaemic episode should be borne in mind. Frequent monitoring of blood glucose and appropriate reduction of sulphonylurea dosage is recommended during coadministration.
Tacrolimus
There have been reports of an interaction when fluconazole is given concomitantly with tacrolimus, leading to increase serum levels of tacrolimus up to 5 times due to inhibition of tacrolimus metabolism through CYP3A4 in the intestines. No significant pharmacokinetic changes have been observed when tacrolimus is given intravenously. There have been reports of nephrotoxicity in patients to whom fluconazole and tacrolimus were coadministered. Patients receiving the two concomitantly should be carefully monitored and dosage of orally administered tacrolimus should be decreased depending on tacrolimus concentration.
The use of fluconazole in patients concurrently taking astemizole, rifabutin, tacrolimus, or other drugs metabolised by the cytochrome P450 system may be associated with elevations in serum levels of these drugs. In the absence of definitive information, caution should be used when co-administering fluconazole. Patients should be carefully monitored.
Theophylline
In a placebo controlled interaction study, the administration of fluconazole 200mg for 14 days resulted in an 18% decrease in the mean plasma clearance of theophylline. Patients who are receiving high doses of theophylline or who are otherwise at increased risk for theophylline toxicity should be observed for theophylline toxicity while receiving fluconazole, and the therapy modified if signs of toxicity develop.
Vinca Alkaloids
Although not studied, fluconazole may increase the plasma levels of vinca alkaloids (e.g. vincristine and vinblastine) and lead to neurotoxicity, which is possibly due to an inhibitory effect on CYP3A4.
Vitamin A
Based on a case-report in one patient receiving combination therapy with all-trans-retinoid acid (an acid form of vitamin A) and fluconazole, CNS related undesirable effects have developed in the form of pseudotumour cerebri, which disappeared after discontinuation of fluconazole treatment. This combination may be used but the incidence of CNS related undesirable effects should be borne in mind.
Zidovudine
Two kinetic studies resulted in increased levels of zidovudine most likely caused by the decreased conversion of zidovudine to its major metabolite. One study determined zidovudine levels in AIDS or ARC patients before and following fluconazole 200mg daily for 15 days. There was a significant increase in zidovudine AUC (20%). A second randomised, two-period, two-treatment cross-over study examined zidovudine levels in HIV infected patients. On two occasions, 21 days apart, patients received zidovudine 200mg every 8 hours either with or without fluconazole 400mg daily for 7 days. The AUC of zidovudine significantly increased (74%) during coadministration with fluconazole. Patients receiving this combination should be monitored for the development of zidovudine-related adverse events. Dosage reduction of Zidovudine may be considered.
Interaction studies have shown that when oral fluconazole is co-administered with food, cimetidine, antacids or following total body irradiation for bone marrow transplantation, no clinically significant impairment of fluconazole absorption occurs.
Endogenous steroid
Fluconazole 50mg daily does not affect endogenous steroid levels in females: 200 - 400mg daily has no clinically significant effect on endogenous steroid levels or on ACTH stimulated response in healthy male volunteers.
Physicians should be aware that drug-drug interaction studies with other medications have not been conducted, but that such interactions may occur.
4.6 Pregnancy and lactation
There are no adequate and well controlled studies in pregnant women. There have been reports of multiple congenital abnormalities in infants whose mothers were being treated for 3 or more months with high doses (400 -800mg/day) of fluconazole for coccidioidomycosis. The relationship between fluconazole and these events is uncertain. Accordingly, fluconazole should not be used in pregnancy, or in women of childbearing potential, unless adequate contraception is employed or if the patient has severe or potentially life-threatening fungal infections in whom fluconazole may be used if the anticipated benefit outweighs the possible risk to the foetus.
Animal studies show teratogenic effects (see section 5.3)
Fluconazole is present in human breast milk at concentrations similar to plasma, hence its use in nursing mothers is not recommended.
4.7 Effects on ability to drive and use machines
Experience with fluconazole indicates that therapy is unlikely to impair a patient’s ability to drive or use machinery.
When driving vehicles or operating machines it should be taken into account that occasionally dizziness or seizures may occur.
4.8 Undesirable effects
Fluconazole is generally well tolerated. The most common side effects observed during clinical trials and associated with fluconazole are:
Central and Peripheral Nervous System Headache
Dermatological Rash
Gastrointestinal Abdominal pain, diarrhoea, flatulence, nausea.
In some patients, particularly those with serious underlying diseases such as AIDS and cancer, changes in renal and haematological function test results and hepatic abnormalities have been observed during treatment with fluconazole and comparative agents, but the clinical significance and relationship to treatment is uncertain. (See Section 4.4, ‘Special warning and precautions for use’.).
The following undesirable effects have been observed and reported during treatment with fluconazole and with the following frequencies: Very common (>1/10); common (>1/100 to <1/10); uncommon (>1/1000, <1/100), rare (>1/10000, <1/1000) and very rare (>1/10000), not known (cannot be estimated from the available data).
|
System Organ Class |
Frequency |
Undesirable effects |
|
Blood and the lymphatic system |
Rare |
Agranulocytosis, leukopenia, neutropenia, thrombocytopenia |
|
Immune system disorders |
Rare |
Anaphylaxis |
|
Metabolism and nutrition disorders |
Uncommon |
Hypokalaemia |
|
Rare |
Hypertriglyceredaemia, hypercholeterolaemia | |
|
Psychiatric disorders |
Uncommon |
Insomnia, somnolence |
|
Nervous system disorders |
Common |
Headache |
|
Uncommon |
Seizures, dizziness, paraesthesia, |
|
taste perversion | ||
|
Rare |
Tremor | |
|
Ear and labyrinth disorders |
Uncommon |
Vertigo |
|
Cardiac disorders |
Rare |
Torsade de pointes, QT prolongation |
|
Gastrointestinal disorders |
Common |
Abdominal pain, diarrhoea, nausea, vomiting |
|
Uncommon |
Dyspepsia, flatulence, dry mouth | |
|
Hepato-biliary disorders |
Common |
Alanine aminotransferase increased, aspartate aminotransferase increased, blood alkaline phosphatise increased |
|
Uncommon |
Cholestasis, jaundice, bilirubin increased | |
|
Rare |
Hepatic failure including rare cases of fatalities, hepatocellular necrosis, hepatitis, hepatocellular damage | |
|
Skin and subcutaneous tissue disorders |
Common |
Rash |
|
Uncommon |
Pruritus, urticaria, increased sweating, drug eruption | |
|
Rare |
Toxic epidermal necrolysis, Stevens-Johnson syndrome, acute generalised exanthematous pustulosis, dermatitis exfoliative, angioedema, face oedema, alopeica | |
|
Musculoskeletal, connective tissue and bone disorders |
Uncommon |
Myalgia |
|
General disorders and administration site conditions |
Uncommon |
Fatigue, malaise, asthenia, fever |
Paediatric Population
The pattern and incidence of side effects and laboratory abnormalities recorded during paediatric clinical trials are comparable to those seen in adults.
4.9 Overdose
There has been a reported case of overdosage with fluconazole. A 42 year old patient infected with HIV developed hallucinations and exhibited paranoid behaviour after reportedly ingesting 8200mg of fluconazole, unverified by his physician. The patient was hospitalised and his condition resolved within 48 hours.
In the event of overdosage, supportive measures and symptomatic treatment, with gastric lavage if necessary, may be adequate.
As fluconazole is largely excreted in the urine, forced volume diuresis would probably increase the elimination rate. A three hour haemodialysis session decreases plasma levels by approximately 50%.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Fluconazole, a member of the triazole class of antifungal agents, is a potent and selective inhibitor of fungal enzymes necessary for the synthesis of ergosterol.
Fluconazole shows little pharmacological activity in a wide range of animal studies. Some prolongation of pentobarbitone sleeping times in mice (p.o.), increased mean arterial and left ventricular blood pressure and increased heart rate in anaesthetised cats (i.v.) occurred. Inhibition of rat ovarian aromatase was observed at high concentrations.
Fluconazole is highly specific for fungal cytochrome P-450 dependent enzymes. Fluconazole 50mg daily given for up to 28 days has been shown not to affect testosterone plasma concentrations in males or steroid concentrations in females of child-bearing age. Fluconazole 200-400mg daily has no clinically significant effect on endogenous steroid levels or on ACTH stimulated response in healthy male volunteers. Interaction studies with antipyrine indicate that single or multiple doses of fluconazole 50mg do not affect its metabolism.
There have been reports of cases of superinfection with Candida species other than C.albicans, which are often inherently not susceptible to fluconazole (e.g. Candida krusei). Such cases may require alternative antifungal therapy.
5.2 Pharmacokinetic properties
The pharmacokinetic properties of fluconazole are similar following administration by the intravenous or oral route. After oral administration fluconazole is well absorbed and plasma levels (and systemic bioavailability) are over 90% of the levels achieved after intravenous administration. Oral administration is not affected by concomitant food intake. Peak plasma concentrations in the fasting state occur between 0.5 - 1.5 hours post-dose with a plasma elimination half-life of approximately 30 hours. Plasma concentrations are proportional to dose. Ninety percent steady-state levels are reached by day 4 - 5 with multiple once daily dosing.
The administration of a higher dose on the first day, double that of the normal daily dose, raises plasma levels to approximately 90% steady-state levels by the second day.
The apparent volume of distribution approximates to total body water. Fluconazole achieves good penetration in all body fluids studied. The levels of fluconazole in saliva and sputum are similar to plasma levels. In patients with fungal meningitis, fluconazole levels in the CSF are approximately 80% of the corresponding plasma levels. High skin concentrations of fluconazole, above serum concentrations, are achieved in the stratum corneum, epidermis-dermis and eccrine sweat. Fluconazole accumulates in the stratum corneum. Plasma protein binding is low (11-12%).
The major route of excretion is renal, with approximately 80% of the administered dose appearing in the urine as unchanged drug. Fluconazole clearance is proportional to creatinine clearance. There is no evidence of circulating metabolites.
Its long clearance plasma elimination half-life makes it possible to administer a single dose in the treatment of genital candidiasis and a daily dose in the treatment of other indications.
5.3 Preclinical safety data
Reproductive toxicity Increases in fetal anatomical variants (supernumerary ribs, renal pelvis dilation) and delays in ossification were observed at 25 and 50mg/kg and higher doses. At doses from 80mg/kg to 320mg/kg embryolethality in rats was increased and fetal abnormalities included wavy ribs, cleft palate and abnormal cranio-facial ossification.
Carcinogenesis Fluconazole showed no evidence of carcinogenic potential in mice and rats treated orally for 24 months at doses of 2.5, 5 or 10mg/kg/day. Male rats treated with 5 and 10mg/kg/day had an increased incidence of hepatocellular adenomas.
Mutagenesis Fluconazole, with or without metabolic activation, was negative in tests for mutagenicity in 4 strains of S.typhimurium and in the mouse lymphoma L5178Y system. Cytogenetic studies in vivo (murine bone marrow cells, following oral administration of fluconazole) and in vitro (human lymphocytes exposed to fluconazole at 1000pg/ml) showed no evidence of chromosomal mutations.
Impairment of fertility Fluconazole did not affect the fertility of male or female rats treated orally with daily doses of 5, 10 or 20mg/kg or with parenteral doses of 5, 25 or 75mg/kg, although the onset of parturition was slightly delayed at 20mg/kg p.o. In an intravenous perinatal study in rats at 5, 20 and 40mg/kg, dystocia and prolongation of parturition were observed in a few dams at 20mg/kg and 40mg/kg, but not at 5mg/kg. The disturbances in parturition were reflected by a slight increase in the number of still-born pups and decrease of neonatal survival at these doses. The affects on parturition in rats are consistent with the species specific oestrogen-lowering property produced by high doses of fluconazole. Such a hormone change has not been observed in women treated with fluconazole.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
lactose monohydrate
microcrystalline cellulose pregelatinized maize starch colloidal anhydrous silica magnesium stearate sodium lauryl sulphate
The capsule shells contain: titanium dioxide E171 quinoline yellow E104 yellow iron oxide E172 patent blue V E131 gelatin.
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
36 months.
6.4 Special precautions for storage
No special precautions for storage.
6.5 Nature and contents of container
PVC/ Aluminium blisters containing 7 capsules.
6.6 Special precautions for disposal
Not applicable.
7 MARKETING AUTHORISATION HOLDER
Medreich Plc Warwick House Plane Tree Crescent Feltham TW13 7HF
DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
21/05/2004 / 27/04/2009
10
DATE OF REVISION OF THE TEXT
05/02/2014